PI: Hugo R. Rosen, MD/ Denver VA Title of Merit Review Grant: Functional attributes of CD8+ T cells in recovery of hepatitis C virus infection Approximately 200 million throughout the world have chronic HCV infection. HCV persists in up to 80% of people infected. In the US alone, the burden over the next 10- 20 years is expected to reach over $10 billion in direct medical costs and double this in overall societal costs. HCV is a leading etiology of liver cancer and cause for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (~50%) fail to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. An understanding of HCV-host interactions is required to combat this virus and to develop improved therapies. Although data derived from the earliest stages of infection provide the greatest mechanistic insights, acute HCV is often unrecognized because symptoms are usually mild or absent. Detailed prospective studies of acute and evolving HCV infection are required to delineate the role of escape mutations in HCV persistence, as well as to define the immunological and virological factors governing viral evolution. In particular, careful dissection of these factors will be critical to the design of any effective T-cell based therapy. PUBLIC HEALTH RELEVANCE: Project Narrative The importance of hepatitis C virus (HCV) in the VA population cannot be overstated: whereas the incidence of HCV in the general population is approximately 2%, the point prevalence among VA patients has been reported to range from 18%-35%. The growing awareness of its importance is reflected in the mandate by the Department of Veterans Affairs to perform HCV testing on all veterans at risk for the disease. Disease modeling predicted a surge in HCV-related morbidity and mortality over the first two decades of this century, which is now being realized. HCV-related complications including cirrhosis, hepatocellular (liver cell) cancer and need for liver transplantation, have tremendous health care and economic ramifications within the VA. Moreover, despite the improving efficacy of antiviral therapies, studies indicate that only a minority of patients in VA clinics have ever received antiviral therapy because of a number of important barriers. Thus, enhanced understanding of how the immune system controls, or more frequently fails to control, HCV infection is sorely required for the VA population. Selected Bibliography: Fimmel CJ. Doing battle with HCV. Am J Gastroenterol 2000; 95: 582-583. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003 Apr;9(4):331-8 Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP. Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol. 2007 Apr;5(4):508- 12. Epub 2007 Mar 26 Ho SB, Groessl E, Dollarhide A, Robinson S, Kravetz D, Dieperink E. Management of chronic hepatitis C in veterans: the potential of integrated care models. Am J Gastroenterol. 2008 Jul;103(7):1810-23.